PL209572B1 - Kompozycja farmaceutyczna zawierająca podstawione azaindole, podstawione azaindole i ich farmaceutyczne zastosowania - Google Patents
Kompozycja farmaceutyczna zawierająca podstawione azaindole, podstawione azaindole i ich farmaceutyczne zastosowaniaInfo
- Publication number
- PL209572B1 PL209572B1 PL355819A PL35581900A PL209572B1 PL 209572 B1 PL209572 B1 PL 209572B1 PL 355819 A PL355819 A PL 355819A PL 35581900 A PL35581900 A PL 35581900A PL 209572 B1 PL209572 B1 PL 209572B1
- Authority
- PL
- Poland
- Prior art keywords
- pyrrolo
- methyl
- compound
- compounds
- pyrazin
- Prior art date
Links
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 title claims description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 406
- 239000000203 mixture Substances 0.000 claims abstract description 163
- 150000003839 salts Chemical class 0.000 claims abstract description 68
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 54
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 49
- 239000001257 hydrogen Substances 0.000 claims abstract description 42
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 7
- -1 hydroxy, phenyl Chemical group 0.000 claims description 89
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 48
- 238000011282 treatment Methods 0.000 claims description 41
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- 108091000080 Phosphotransferase Proteins 0.000 claims description 21
- 102000020233 phosphotransferase Human genes 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical group 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 230000002401 inhibitory effect Effects 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 150000002431 hydrogen Chemical group 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 206010003246 arthritis Diseases 0.000 claims description 9
- MIJMZVTYIXYSDK-UHFFFAOYSA-N 6-(5-methoxy-1-methylindol-3-yl)-5h-pyrrolo[2,3-b]pyrazine Chemical compound C1=CN=C2NC(C3=CN(C)C4=CC=C(C=C43)OC)=CC2=N1 MIJMZVTYIXYSDK-UHFFFAOYSA-N 0.000 claims description 8
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- XQYJBGKMIPFFJS-UHFFFAOYSA-N 6-(4-methoxyphenyl)-5h-pyrrolo[2,3-b]pyrazine Chemical compound C1=CC(OC)=CC=C1C1=CC2=NC=CN=C2N1 XQYJBGKMIPFFJS-UHFFFAOYSA-N 0.000 claims description 6
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 208000006673 asthma Diseases 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- ONJMAXYFHBVNTH-UHFFFAOYSA-N 6-phenyl-5h-pyrrolo[2,3-b]pyrazine Chemical compound N1C2=NC=CN=C2C=C1C1=CC=CC=C1 ONJMAXYFHBVNTH-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- BEVMNJLOWZOCEF-UHFFFAOYSA-N 2-methyl-6-phenyl-5h-pyrrolo[2,3-b]pyrazine Chemical compound C=1C2=NC(C)=CN=C2NC=1C1=CC=CC=C1 BEVMNJLOWZOCEF-UHFFFAOYSA-N 0.000 claims description 3
- WOSGPBFDGVRZKT-UHFFFAOYSA-N 3-methyl-6-phenyl-5h-pyrrolo[2,3-b]pyrazine Chemical compound N1C2=NC(C)=CN=C2C=C1C1=CC=CC=C1 WOSGPBFDGVRZKT-UHFFFAOYSA-N 0.000 claims description 3
- YGINNQXWHUWSHG-UHFFFAOYSA-N 6-(2-chlorophenyl)-5h-pyrrolo[2,3-b]pyrazine Chemical compound ClC1=CC=CC=C1C1=CC2=NC=CN=C2N1 YGINNQXWHUWSHG-UHFFFAOYSA-N 0.000 claims description 3
- VFKHBJJSGUYSDC-UHFFFAOYSA-N 6-(4-chlorophenyl)-5h-pyrrolo[2,3-b]pyrazine Chemical compound C1=CC(Cl)=CC=C1C1=CC2=NC=CN=C2N1 VFKHBJJSGUYSDC-UHFFFAOYSA-N 0.000 claims description 3
- QLBVJDQLXOSSMT-UHFFFAOYSA-N 7-methyl-6-phenyl-5h-pyrrolo[2,3-b]pyrazine Chemical compound N1C2=NC=CN=C2C(C)=C1C1=CC=CC=C1 QLBVJDQLXOSSMT-UHFFFAOYSA-N 0.000 claims description 3
- UGHVSNVFYBZSLH-UHFFFAOYSA-N [1-[1-methyl-3-(5h-pyrrolo[2,3-b]pyrazin-6-yl)indol-5-yl]oxycyclobutyl]methanol Chemical compound C=1C=C2N(C)C=C(C=3NC4=NC=CN=C4C=3)C2=CC=1OC1(CO)CCC1 UGHVSNVFYBZSLH-UHFFFAOYSA-N 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 1
- GDTFIRYHAYIXIP-UHFFFAOYSA-N methoxycyclobutane Chemical group COC1CCC1 GDTFIRYHAYIXIP-UHFFFAOYSA-N 0.000 claims 1
- VXPLXMJHHKHSOA-UHFFFAOYSA-N propham Chemical group CC(C)OC(=O)NC1=CC=CC=C1 VXPLXMJHHKHSOA-UHFFFAOYSA-N 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 abstract description 22
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 19
- 229940002612 prodrug Drugs 0.000 abstract description 16
- 239000000651 prodrug Substances 0.000 abstract description 16
- 239000012453 solvate Substances 0.000 abstract description 10
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 9
- 102000001253 Protein Kinase Human genes 0.000 abstract description 8
- 125000003342 alkenyl group Chemical group 0.000 abstract description 8
- 108060006633 protein kinase Proteins 0.000 abstract description 8
- 125000005843 halogen group Chemical group 0.000 abstract description 7
- 125000002252 acyl group Chemical group 0.000 abstract description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract description 3
- 229910014033 C-OH Inorganic materials 0.000 abstract 1
- 229910014570 C—OH Inorganic materials 0.000 abstract 1
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 384
- 238000000034 method Methods 0.000 description 235
- 239000007787 solid Substances 0.000 description 232
- 239000000243 solution Substances 0.000 description 178
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 165
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 142
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 125
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 118
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 108
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 92
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 71
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 68
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 68
- 239000011541 reaction mixture Substances 0.000 description 63
- 238000005481 NMR spectroscopy Methods 0.000 description 56
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 54
- 210000004027 cell Anatomy 0.000 description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- 239000002253 acid Substances 0.000 description 51
- 238000004128 high performance liquid chromatography Methods 0.000 description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- 238000003756 stirring Methods 0.000 description 44
- 239000000377 silicon dioxide Substances 0.000 description 42
- 210000004072 lung Anatomy 0.000 description 41
- IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 238000004809 thin layer chromatography Methods 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 34
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 34
- 235000019341 magnesium sulphate Nutrition 0.000 description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 239000000427 antigen Substances 0.000 description 32
- 108091007433 antigens Proteins 0.000 description 32
- 102000036639 antigens Human genes 0.000 description 32
- 239000012267 brine Substances 0.000 description 28
- 230000000694 effects Effects 0.000 description 28
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 230000005764 inhibitory process Effects 0.000 description 26
- VAJOSPMTARTPKN-UHFFFAOYSA-N 2-[5-methoxy-3-(5h-pyrrolo[2,3-b]pyrazin-6-yl)indol-1-yl]-1-morpholin-4-ylethanone Chemical compound C1=C(C=2NC3=NC=CN=C3C=2)C2=CC(OC)=CC=C2N1CC(=O)N1CCOCC1 VAJOSPMTARTPKN-UHFFFAOYSA-N 0.000 description 24
- 230000000875 corresponding effect Effects 0.000 description 23
- 239000012442 inert solvent Substances 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 230000002829 reductive effect Effects 0.000 description 22
- 238000010992 reflux Methods 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 235000011152 sodium sulphate Nutrition 0.000 description 22
- 108010058846 Ovalbumin Proteins 0.000 description 20
- 239000000284 extract Substances 0.000 description 20
- 239000012299 nitrogen atmosphere Substances 0.000 description 20
- 229940092253 ovalbumin Drugs 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- 241000700159 Rattus Species 0.000 description 18
- 150000001721 carbon Chemical group 0.000 description 18
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 241001465754 Metazoa Species 0.000 description 17
- 239000002585 base Substances 0.000 description 17
- 239000000725 suspension Substances 0.000 description 17
- 108090000461 Aurora Kinase A Proteins 0.000 description 16
- 102100032311 Aurora kinase A Human genes 0.000 description 16
- 102000016621 Focal Adhesion Protein-Tyrosine Kinases Human genes 0.000 description 16
- 108010067715 Focal Adhesion Protein-Tyrosine Kinases Proteins 0.000 description 16
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- 210000001519 tissue Anatomy 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 14
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 230000004044 response Effects 0.000 description 14
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
- 150000001204 N-oxides Chemical class 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 13
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 239000002609 medium Substances 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- 239000012312 sodium hydride Substances 0.000 description 13
- 229910000104 sodium hydride Inorganic materials 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 239000012634 fragment Substances 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 230000008569 process Effects 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 10
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 10
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 10
- 229910052794 bromium Inorganic materials 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 9
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- 239000012507 Sephadex™ Substances 0.000 description 9
- 238000011685 brown norway rat Methods 0.000 description 9
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- 238000000921 elemental analysis Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
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- 150000004677 hydrates Chemical class 0.000 description 9
- 239000011259 mixed solution Substances 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- CHIFTAQVXHNVRW-UHFFFAOYSA-N 1h-indole-3-carbonitrile Chemical compound C1=CC=C2C(C#N)=CNC2=C1 CHIFTAQVXHNVRW-UHFFFAOYSA-N 0.000 description 8
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 8
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 231100000673 dose–response relationship Toxicity 0.000 description 8
- 125000004494 ethyl ester group Chemical group 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- CAWHJQAVHZEVTJ-UHFFFAOYSA-N methylpyrazine Chemical compound CC1=CN=CC=N1 CAWHJQAVHZEVTJ-UHFFFAOYSA-N 0.000 description 8
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- 235000010446 mineral oil Nutrition 0.000 description 8
- 210000000440 neutrophil Anatomy 0.000 description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 8
- KYWSGFFFDGCSES-UHFFFAOYSA-N 1-methyl-3-(5h-pyrrolo[2,3-b]pyrazin-6-yl)indol-5-ol Chemical compound C12=CC(O)=CC=C2N(C)C=C1C1=CC2=NC=CN=C2N1 KYWSGFFFDGCSES-UHFFFAOYSA-N 0.000 description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 7
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 7
- 102000000551 Syk Kinase Human genes 0.000 description 7
- 108010016672 Syk Kinase Proteins 0.000 description 7
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- 229960000583 acetic acid Drugs 0.000 description 7
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 7
- 125000003710 aryl alkyl group Chemical group 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 7
- 210000003979 eosinophil Anatomy 0.000 description 7
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- 229910052740 iodine Inorganic materials 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
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- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
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- 230000004614 tumor growth Effects 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
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- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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GBGB9930698.7A GB9930698D0 (en) | 1999-12-24 | 1999-12-24 | Chemical compounds |
US21581800P | 2000-07-05 | 2000-07-05 | |
PCT/GB2000/004993 WO2001047922A2 (en) | 1999-12-24 | 2000-12-27 | Azaindoles |
Publications (2)
Publication Number | Publication Date |
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PL355819A1 PL355819A1 (en) | 2004-05-17 |
PL209572B1 true PL209572B1 (pl) | 2011-09-30 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PL355819A PL209572B1 (pl) | 1999-12-24 | 2000-12-27 | Kompozycja farmaceutyczna zawierająca podstawione azaindole, podstawione azaindole i ich farmaceutyczne zastosowania |
Country Status (27)
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US (2) | US6770643B2 (no) |
EP (2) | EP1990343B1 (no) |
JP (1) | JP5436507B2 (no) |
KR (2) | KR100910488B1 (no) |
CN (2) | CN100379734C (no) |
AP (2) | AP1917A (no) |
AU (1) | AU777717B2 (no) |
BG (2) | BG66066B1 (no) |
BR (1) | BR0017038A (no) |
CA (2) | CA2395593C (no) |
CY (1) | CY1110951T1 (no) |
CZ (2) | CZ301750B6 (no) |
DZ (1) | DZ3377A1 (no) |
EA (1) | EA005212B1 (no) |
EE (1) | EE05180B1 (no) |
HK (1) | HK1050191B (no) |
HR (1) | HRP20020547B1 (no) |
HU (1) | HUP0203895A3 (no) |
IL (3) | IL150388A0 (no) |
MA (1) | MA26857A1 (no) |
MX (1) | MXPA02006338A (no) |
NO (2) | NO323766B1 (no) |
NZ (1) | NZ519121A (no) |
OA (1) | OA12514A (no) |
PL (1) | PL209572B1 (no) |
SK (2) | SK287882B6 (no) |
WO (1) | WO2001047922A2 (no) |
Families Citing this family (137)
Publication number | Priority date | Publication date | Assignee | Title |
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CZ301750B6 (cs) | 1999-12-24 | 2010-06-09 | Aventis Pharma Limited | Bicyklický pyrrolový derivát, jeho použití pri výrobe léciva, farmaceutická kompozice tento derivát obsahující a pro použití pri lécení |
EP1363705B9 (en) * | 2001-02-02 | 2012-11-07 | Bristol-Myers Squibb Company | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
GB0108770D0 (en) | 2001-04-06 | 2001-05-30 | Eisai London Res Lab Ltd | Inhibitors |
GB0115109D0 (en) * | 2001-06-21 | 2001-08-15 | Aventis Pharma Ltd | Chemical compounds |
WO2003000690A1 (en) * | 2001-06-25 | 2003-01-03 | Aventis Pharmaceuticals Inc. | Synthesis of heterocyclic compounds employing microwave technology |
EP2335700A1 (en) * | 2001-07-25 | 2011-06-22 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis C virus polymerase inhibitors with a heterobicylic structure |
US20030158195A1 (en) | 2001-12-21 | 2003-08-21 | Cywin Charles L. | 1,6 naphthyridines useful as inhibitors of SYK kinase |
US6884889B2 (en) * | 2002-03-25 | 2005-04-26 | Bristol-Myers Squibb Co. | Processes for the preparation of antiviral 7-azaindole derivatives |
JP2005534619A (ja) * | 2002-03-28 | 2005-11-17 | エーザイ株式会社 | C−junn−末端キナーゼ阻害剤としてのアザインドール |
KR20040111445A (ko) * | 2002-03-28 | 2004-12-31 | 에자이 가부시키가이샤 | 신경퇴행성 질환 치료용 c─Jun N─말단 키나아제억제제로서의 7─아자인돌 |
US20050124620A1 (en) * | 2002-04-09 | 2005-06-09 | Martyn Frederickson | Pharmaceutical compounds |
AU2003224257A1 (en) * | 2002-04-09 | 2003-10-27 | Astex Technology Limited | Heterocyclic compounds and their use as modulators of p38 map kinase |
TW200307542A (en) * | 2002-05-30 | 2003-12-16 | Astrazeneca Ab | Novel compounds |
SE0201635D0 (sv) | 2002-05-30 | 2002-05-30 | Astrazeneca Ab | Novel compounds |
SE0202241D0 (sv) | 2002-07-17 | 2002-07-17 | Astrazeneca Ab | Novel Compounds |
EP1388541A1 (en) | 2002-08-09 | 2004-02-11 | Centre National De La Recherche Scientifique (Cnrs) | Pyrrolopyrazines as kinase inhibitors |
EP1545515A1 (en) | 2002-08-12 | 2005-06-29 | Sugen, Inc. | 3-pyrrolyl-pyridopyrazoles and 3-pyrrolyl-indazoles as novel kinase inhibitors |
SE0202464D0 (sv) * | 2002-08-14 | 2002-08-14 | Astrazeneca Ab | Use of compounds |
WO2004063181A1 (en) * | 2003-01-03 | 2004-07-29 | Genzyme Corporation | Urea derivatives and their use as anti-inflammatory agents |
US7223785B2 (en) | 2003-01-22 | 2007-05-29 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
US7098231B2 (en) * | 2003-01-22 | 2006-08-29 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
GB0305142D0 (en) | 2003-03-06 | 2003-04-09 | Eisai London Res Lab Ltd | Synthesis |
EP2295433A3 (en) * | 2003-03-06 | 2011-07-06 | Eisai R&D Management Co., Ltd. | JNK inhibitors |
SE0300908D0 (sv) | 2003-03-31 | 2003-03-31 | Astrazeneca Ab | Azaindole derivatives, preparations thereof, uses thereof and compositions containing them |
SE0301372D0 (sv) * | 2003-05-09 | 2003-05-09 | Astrazeneca Ab | Novel compounds |
EP1628975A2 (en) | 2003-05-16 | 2006-03-01 | Eisai Co., Ltd. | Jnk inhibitors |
SE0301569D0 (sv) | 2003-05-27 | 2003-05-27 | Astrazeneca Ab | Novel compounds |
RU2356889C2 (ru) | 2003-07-17 | 2009-05-27 | Плекссикон, Инк. | Соединения, являющиеся активными по отношению к рецепторам, активируемым пролифератором пероксисом |
SE0302232D0 (sv) | 2003-08-18 | 2003-08-18 | Astrazeneca Ab | Novel Compounds |
SE0303180D0 (sv) * | 2003-11-26 | 2003-11-26 | Astrazeneca Ab | Novel compounds |
JP2007514759A (ja) * | 2003-12-19 | 2007-06-07 | タケダ サン ディエゴ インコーポレイテッド | キナーゼ阻害剤 |
DK1718608T3 (da) * | 2004-02-20 | 2013-10-14 | Boehringer Ingelheim Int | Virale polymeraseinhibitorer |
FR2868422B1 (fr) | 2004-03-31 | 2006-07-14 | Aventis Pharma Sa | Nouveaux derives pyrrolo(2,3-b) pyridine, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de kinases |
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